Autism is currently defined as a single disorder characterized by impairments in communication and social interaction and the presence of restricted interests and repetitive behaviors. However, there is mounting evidence that autism represents a collection of overlapping neurodevelopmental disorders, resulting from a variety of neuroanatomical, neurophysiological, neuroimmunologic and/or genetic abnormalities. The wide range of possible etiologies and the heterogeneity of symptom expression among individuals with autism leads to speculation that there actually are several autisms, i.e., clinically distinct disorders with similar behavioral presentations but different etiologies, clinical course, and treatments. The PDN research program aims to characterize the behavioral and biological manifestations of these patient cohorts and to identify their unique features in order to facilitate development of effective therapeutic and preventive interventions. During the reporting period, this project focused primarily on a longitudinal, phenotyping investigation of 105 young children (ages 1-6 years) with autism, 60 age and sex-matched typically developing controls and a group of 25 children with non-autistic developmental delays. Baseline evaluations have been completed for these subjects and they are returning for periodic follow-up assessments. Data from the baseline evluations are now being analyzed, including examinations of potentially meaningful subgroups of patients, such as the comparisons of children with autism whow have a history of developmental regression and those without (Developmental regression is defined by a significant loss of social and/or communication skills). Our initial findings indicate no significant differences between the regressive and non-regressive subgroups; indeed the most striking finding of the preliminary analyses was that regression appears to be a continuous variable, rather than the dichotomous categories previously described. That is, children with a history of developmental regression have frequently had at least some delays in their early development and those with distinct early developmental delays may also lose some social and communication skills. In addition to the behavioral assessments, the study includes comprehensive medical and developmental histories; neuropsychological, medical and neurological evaluations; assays of blood, urine and cerebrospinal fluid (CSF) samples; and also a variety of specialized studies, including routine and overnight electroencephalograms(EEGs); modified polysomnography to evaluate sleep architecture; and magnetic resonance imaging (MRI scans); genetic assays; and dysmorphology evaluations. Preliminary results from these evaluations have demonstrated that more than one-half of the children have abnormalities of sleep architecture, particularly notable are reductions in the percentage time spent in Rapid Eye Movement (REM) sleep. The low REM findings prompted a small therapeutic trial which is described in a separate project report (MH002914-04 PDNB). As expected, genetic abnormalities were found in approximately 10% of the subjects and the aberrations are being evaluated for clinical significance (that is, are they a potential etiologic factor or merely a clinically insignificant variation.) As the baseline data are being examined, particular attention is being paid to interesting N of 1 or 2 findings - unique physical, behavioral, genetic, neuroimaging or biochemical characteristics of children with autism that might provide clues to etiology or pathogenesis. The goal of the phenotyping investigation is to determine if there are distinct groups of individuals within the spectrum of autistic disorders that share common profiles of biological and/or behavioral characteristics. Identification of such subgroups will provide new avenues for clinical and basic science researchh into the causes and treatments of autism. More information about this study may be found at: http://clinicalstudies.info.nih.gov/detail/A_2006-M-0102.html Three other phenotyping studies are also underway. Each of them shares the goal of providing a deeper understanding of the autism phenotype and its relationship to etiology, clinical course and outcome. The goal of the first study in this group is obvious from its title: Identification of Characteristics Associated with Symptom Remission in Autism. This investigation is comparing children previously diagnosed with autism, whose symptoms have remitted (partially or completed), with a cohort of similarly aged children who received similar interventions but continued to meet criteria for autism. The study aims to identify specific predictors of response in the remitted group, which will lead to the development and application of more effective treatments for the larger cohort of individuals with ASD. The study is actively recruiting children and adolescents with a history of remitted autism and their age-/sex-matched contrast groups. More information about the remitted autism study can be found at: http://clinicaltrials.gov/ct2/show/NCT00938054. The second study is using oxytocin and vasopressin as probes in a functional neuroimaging study of social cognition among young adults with ASD and age-/sex-matched healthy volunteers. This investigation utilizes functional magnetic resonance imaging (fMRI) to assess the impact of the (blinded) administration of oxytocin, vasopressin or placebo on behavior and brain function in response to tasks of social cognition. Comparisons across groups, tasks and drugs will determine if individuals with autism have different patterns of brain activation compared to normal controls, as well as pre and post dose of neuropeptide or placebo, per the experimental design. The investigation will provide greater understanding of the nature of autism's social deficits and the activation patterns may provide important clues into the pathophysiology of the disorder. More information about the fMRI study can be found at http://www.clinicaltrials.gov/ct2/show/NCT01093768?term=autism+oxytocin&rank=3. The most recent PDN phenotyping study is a prospective, longitudinal investigation of toddlers considered to be at-risk for ASD because of the presence of early language delays. This study aims to delineate early communicative impairments that predict ASD and to distinguish these from non-specific markers of non-autistic developmental delays, as well as examining how communication impairments correlate with brain structure and function, as assessed with structural and functional MRI scans, and overnight EEGs. The longitudinal assessments also include comprehensive behavioral assessments desifned to profile strengths and weaknesses in communication and other domains. The goal of these assessments is to identify specific risk and resilience factors for ASD, assessed at the final evaluation at age 3 - 4 years. More information about this study may be found at: http://www.clinicaltrials.gov/ct2/show/NCT01339767?term=toddlers+autism&rank=2